PLatform for Adaptive Trials In Perinatal UnitS - [Core Protocol]

Preterm Birth Clinical Trial

— PLATIPUS  

Official title:

Platform for Adaptive Trials in Perinatal Units (Core Protocol)

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06461429
• Other study ID #: P-CORE-01
• Status: Not yet recruiting
• Phase: N/A
• Start date: February 1, 2025
• Est. completion date: December 31, 2050

Study information

• Verified date: June 2024
• Source: University of Melbourne
• Contact: Clare Whitehead, MBChB, PhD
• Phone: +61
• Email: clarew[@]unimelb.edu.au
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

PLATIPUS is an adaptive platform trial aimed at improving the health of infants born preterm (before 37 weeks' gestation). PLATIPUS will compare how different treatments and care provided to pregnant women and people at risk of preterm birth and infants born preterm affect infant health.

The main questions PLATIPUS aims to answer are:

1. What effect/s do different treatments/care provided to pregnant women and people at risk of preterm birth have on the health of their infants? (Pregnancy domains)

2. What effect/s do different treatments/care given to infants born preterm have on their health ? (Neonatal domains).

This registration record relates to the PLATIPUS Core (or 'master') protocol which provides guidance for the overall running of the trial. Additional appendices will outline the aims, questions, treatments, and activities for each separate research question (domain). Each Domain-Specific Appendix will be registered separately on ClinicalTrials.gov and will link to this record.

Description:

PLATIPUS is a multi-domain, multi-centre international adaptive platform trial and innovative approach to perinatal research.

Preterm birth (birth before 37 weeks' gestation) is a global issue. More than 15 million babies (1 in 10) are born preterm each year. Complications of preterm birth are the leading cause of death and disability among children under five years of age. These contribute to increased risk of all-cause mortality and early death from cardiovascular disease, diabetes and chronic lung disease in later life. There is no single cause of, or pathway to, preterm birth. Treatments during pregnancy aim to prevent or treat complications that can lead to preterm birth in pregnant women and people or reduce the impact of prematurity on neonatal outcomes. Treatments in the neonatal period (period shortly after birth) aim to improve survival and reduce potential morbidities in the preterm infant.

PLATIPUS will initially assess interventions given to pregnant women and people during pregnancy (Participant Group 1) and to preterm infants (Participant Group 2) in the first few days of life. Participants will be randomly allocated to all relevant domains for which they are eligible and provide consent. Using a trial-developed Ordinal Outcome Scale, the effect of pregnancy and/or neonatal interventions on neonatal outcome will be assessed at 42 weeks' post-menstrual age OR at primary hospital discharge, whichever occurs earliest. Secondary outcomes will examine the effect of interventions on individual pregnancy and/or neonatal endpoints, and may be domain-specific. All pregnancy domains will include a 'Maternal Outcome Set' to assess maternal health and intervention safety.

In contrast to conventional clinical trials, PLATIPUS has been designed to examine multiple different treatment options at once within the same platform. Both pregnant and neonatal participants will be randomly assigned to different concurrent treatment options, with an initial focus on treatments already considered as part of clinical care. As the trial advances, novel interventions may also be included. Interventions will be evaluated within domains. A domain is defined as a set of interventions that are intended for a specific health problem or specific therapeutic option.

Bayesian adaptive statistical modelling will be used to evaluate treatment efficacy at regular interim adaptive analyses of the pre-specified outcomes for each intervention in each domain. This will allow determination of the effectiveness of interventions once sufficient data has been accrued, rather than when a pre-specified sample size is reached. Adaptive analyses will compute the posterior probabilities of superiority, futility, inferiority, or equivalence for pre-specified comparisons within domains. Each of these potential conclusions will be pre-defined prior to commencing the intervention domain. Decisions about trial results (e.g., concluding superiority or equivalence) will be based on pre-specified threshold values for posterior probability.

All trial procedures are outlined in the "core" protocol described in this registration. Separate domain protocols with information specific to each intervention included in PLATIPUS will be linked to this registration at separate clinicaltrials.gov records:

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 100000
• Est. completion date: December 31, 2050
• Est. primary completion date: December 31, 2050
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A and older

Eligibility

Potential participants with core platform eligibility AND who meet all domain-specific inclusion criteria and none of the domain-specific exclusion criteria for at least one PLATIPUS domain, will be eligible to 'enrol' in the PLATIPUS trial and randomised to all eligible domains, for which consent has been provided.

CORE PLATFORM ELIGIBILITY - PREGNANCY DOMAINS

Inclusion Criteria: Pregnant women and people must fulfil the following inclusion criteria to be eligible to participate in PLATIPUS:

1. Pregnant and at risk of preterm birth

2. Receiving care at a participating site at the time of eligibility assessment.

3. Meets the eligibility criteria for at least one domain.

Exclusion Criteria: Pregnant women and people who meet the following criteria will be excluded from participation in this trial:

1. Circumstances where death (pregnant woman or person/fetal) is deemed to be imminent and inevitable. The treating team may however decide that providing an opportunity for the pregnant woman or person to participate would be in their and/or their fetus/infant's interest. OR

2. Inability to consent, unless a waiver of consent has been deemed appropriate at domain-level.

CORE PLATFORM ELIGIBILITY - NEONATAL DOMAINS

Inclusion Criteria: Preterm infants must fulfil the following criteria to be eligible to participate in PLATIPUS, infants must be:

1. Born preterm (<37 weeks' gestational age)

2. Receiving care at a participating site at the time of eligibility assessment.

3. Meet the eligibility criteria for at least one domain.

Exclusion Criteria: Preterm infants who meet the following criteria will be excluded from participation in this trial:

1. Circumstances where death (neonatal) is deemed to be imminent and inevitable. The treating team may however decide that providing an opportunity for the infant to participate is in the infant's interest. OR

2. Parental/guardian inability to consent, unless a waiver of consent has been deemed appropriate at domain-level.

DOMAIN-SPECIFIC ELIGIBILITY CRITERIA

Potential participants who meet core platform eligibility criteria will be assessed for eligibility to participate in trial domains available at their hospital. Domain-specific eligibility criteria are outlined in the related Domain-Specific Appendices.

Related Conditions & MeSH terms

• Premature Birth
• Preterm Birth

Intervention

Drug:
• Erythromycin
Antibiotic. Standard of care. Antibiotics will be administered for 7 days or until delivery (whichever is sooner).
• Amoxicillin and Erythromycin
Antibiotic. Antibiotics will be administered for 7 days or until delivery (whichever is sooner).
• Azithromycin
Antibiotic. Antibiotics will be administered for 7 days or until delivery (whichever is sooner).
• Caffeine citrate: Low dose
Lower dose caffeine: 20mg/kg load and 10mg/kg/day maintenance. Standard of care. Caffeine will be administered until at least 34+0 weeks' post-menstrual age, with the aim to cease caffeine by 36+0 weeks' post-menstrual age. Caffeine use beyond 36+0 weeks' post-menstrual age will be open-label.
• Caffeine citrate: Medium dose
Medium dose caffeine: 30mg/kg load and 15 mg/kg/day maintenance. Caffeine will be administered until at least 34+0 weeks' post-menstrual age, with the aim to cease caffeine by 36+0 weeks' post-menstrual age. Caffeine use beyond 36+0 weeks' post-menstrual age will be open-label.
• Caffeine citrate: High dose
Higher dose caffeine: 40mg/kg load and 20mg/kg/day maintenance. Caffeine will be administered until at least 34+0 weeks' post-menstrual age, with the aim to cease caffeine by 36+0 weeks' post-menstrual age. Caffeine use beyond 36+0 weeks' post-menstrual age will be open-label.

Locations

Country	Name	City	State
n/a

Sponsors (11)

Lead Sponsor	Collaborator
University of Melbourne	La Trobe University, Mater Medical Research Institute, Menzies School of Health Research, Monash University, The University of New South Wales, The University of Western Australia, University of Adelaide, University of Auckland, New Zealand, University of Sydney, University of Tasmania

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of participants who progress by at least one level higher on the PLATIPUS Ordinal Outcome Scale	The PLATIPUS-Ordinal Outcome Scale ranks the most severe core short-term infant health outcome in the specified time frame.; Levels 1-15: 1= Well, liveborn infant; 2= Neonatal unit admission for <48 hours; 3= Neonatal unit admission for >/= 48 hours; 4= Non-invasive respiratory support or oxygen therapy for = 4 hours & < 5 days; 5= Non-invasive respiratory support or oxygen therapy >/= 5 days; 6= Mechanical ventilation via endotracheal tube for = 4 hours & <7 days; 7= Mechanical ventilation via endotracheal tube for >/=7 days; 8= Moderate respiratory morbidity; 9=Necrotising enterocolitis AND/OR Sepsis; 10= Severe Respiratory Morbidity; 11= Major Surgery; 12= Brain Injury; 13= TWO of severe respiratory morbidity OR major surgery OR brain injury; 14= Severe respiratory morbidity & major surgery & brain injury; 15 = Death	At any time prior to 42 weeks' postmenstrual age or first discharge home from hospital (whichever is earlier).
Secondary	Number of well liveborn infants	Well, liveborn infants who have not met the diagnostic criteria for worse scale outcomes.; The ordinal outcome scale ranks short-term neonatal outcomes associated with longer-term health in ascending severity. An infant is assigned the outcome that is the highest (worst) for which they have met diagnostic criteria at any time prior to 42 weeks PMA or first hospital discharge (whichever is earlier).	At any time prior to 42 weeks' postmenstrual age or first discharge home from hospital (whichever is earlier).
Secondary	Number of infants admitted to the neonatal unit during primary hospital admission for 48 hours or more.	Infants admitted to the neonatal unit during primary hospital admission for 48 hours or more.	At any time prior to 42 weeks' postmenstrual age or first discharge home from hospital (whichever is earlier).
Secondary	Number of infants admitted to neonatal unit during primary hospital admission for <48 hours.	Infants admitted to any level of neonatal unit during the birth admission, for less than 48 hours.	At any time prior to 42 weeks' postmenstrual age or first discharge home from hospital (whichever is earlier).
Secondary	Number of infants who received non-invasive respiratory support or oxygen therapy for = 4 hours (excluding delivery room) and less than 5 days.	Infants who received non-invasive respiratory support or oxygen therapy for = 4 hours (excluding delivery room) and less than 5 days.	At any time prior to 42 weeks' postmenstrual age or first discharge home from hospital (whichever is earlier).
Secondary	Number of infants who received non-invasive respiratory support or oxygen therapy for 5 days or more.	Infants who received non-invasive respiratory support or oxygen therapy for 5 days or more.	At any time prior to 42 weeks' postmenstrual age or first discharge home from hospital (whichever is earlier).
Secondary	Number of infants who received mechanical ventilation via endotracheal tube for = 4 hours (excluding delivery room) and <7 days.	Infants who received mechanical ventilation via endotracheal tube for = 4 hours (excluding delivery room) and <7 days.	At any time prior to 42 weeks' postmenstrual age or first discharge home from hospital (whichever is earlier).
Secondary	Total duration of infant's first hospitalisation, in days	Total duration of infant's first hospitalisation, in days. An average of three months.	From date of infant birth to date of first discharge home from hospital (or date of death, whichever occurs earlier), assessed up to 12 months.
Secondary	Number of infants who received mechanical ventilation via endotracheal tube for 7 days or more.	Infants who received mechanical ventilation via endotracheal tube for 7 days or more.	At any time prior to 42 weeks' postmenstrual age or first discharge home from hospital (whichever is earlier).
Secondary	Number of infants with moderate respiratory morbidity.	Infants with a gestational age <37 weeks who received oxygen therapy at 40 weeks' postmenstrual age.	At any time prior to 42 weeks' postmenstrual age or first discharge home from hospital (whichever is earlier).
Secondary	Number of infants with necrotising enterocolitis OR sepsis.	A. Necrotising enterocolitis (NEC) Infants with imaging suggestive of NEC (radiograph or ultrasound) including pneumatosis intestinalis, portal venous gas, persistently dilated loop of bowel, AND broad-spectrum antibiotics for =7 days.; Note: any infant requiring surgery for NEC should be ranked as 'major surgery'.; OR; B. Sepsis Infants with organism isolated in blood or Cerebral Spinal Fluid (CSF) (via culture or polymerase chain reaction (PCR)) AND treatment with antimicrobials for 5 days or more.	At any time prior to 42 weeks' postmenstrual age or first discharge home from hospital (whichever is earlier).
Secondary	Number of infants with severe respiratory morbidity.	Infants with severe respiratory morbidity defined as one or more of the following: Gestational age <37 weeks and respiratory support (HF >2L/min, Continuous Positive Airway Pressure (CPAP), Non-Invasive Positive Pressure Ventilation (NIPPV), Nasal High Frequency Oscillatory Ventilation (nHFOV), mechanical ventilation via an endotracheal tube) for more than 24 hours at 40 weeks' postmenstrual age.; Discharged home with oxygen and/or respiratory support.; Tracheostomy.	At any time prior to 42 weeks' postmenstrual age or first discharge home from hospital (whichever is earlier).
Secondary	Number of participants who underwent major surgery.	Infants who underwent major surgery, defined as one of the following: Laparotomy; Thoracotomy; Craniotomy; Ligation of a ductus arteriosus; Required surgery for NEC.; Excludes inguinal hernia repair, tracheostomy, neurosurgical intervention for post hemorrhagic hydrocephalus.	At any time prior to 42 weeks' postmenstrual age or first discharge home from hospital (whichever is earlier).
Secondary	Any breastmilk feeding (yes/no) at 42 weeks' postmenstrual age or day of first discharge home from hospital (whichever occurs earliest)	Any breastmilk feeding at 42 weeks' postmenstrual age or on day of first hospital discharge home (whichever occurs earliest). Data will be collected as yes/no.	At 42 weeks' postmenstrual or on day of first discharge home from hospital (whichever occurs earliest)
Secondary	Number of infants with TWO of Brain Injury OR Major Surgery OR Severe Respiratory Morbidity, who did not experience any worse scale outcomes.	Infants that meet the definition of TWO of Brain Injury OR Major Surgery OR Severe Respiratory Morbidity (as defined in Scale Categories 10, 11 and 12)	At any time prior to 42 weeks' postmenstrual age or first discharge home from hospital (whichever is earlier).
Secondary	Number of infants with Brain injury AND Major surgery AND Severe respiratory morbidity.	Infants that meet the definition of Brain Injury AND Major Surgery AND Severe Respiratory Morbidity (as defined in Scale Categories 10, 11 and 12)	At any time prior to 42 weeks' postmenstrual age or first discharge home from hospital (whichever is earlier).
Secondary	Number of infants with brain injury.	Infants with brain injury can be diagnosed on ultrasound or magnetic resonance imaging. Brain injury includes one or more of the following: a. Major intraventricular haemorrhage, unilateral or bilateral, defined as i. Papile Grade 3 or 4 AND/OR ii. Moderate-severe periventricular haemorrhagic infarction b. Cystic periventricular leukomalacia, unilateral or bilateral c. Moderate or severe white matter injury on MRI at near-term or term equivalent age d. Any cerebellar haemorrhage e. Other major ischaemic injury such as arterial stroke or hypoxic ischaemic injury f. Post haemorrhagic hydrocephalus requiring drainage.	At any time prior to 42 weeks' postmenstrual age or first discharge home from hospital (whichever is earlier).
Secondary	Number of infants who died	Death includes fetal death in utero, intrapartum stillbirth, neonatal death, and death before hospital discharge of a liveborn infant.	At any time prior to 42 weeks' postmenstrual age or first hospital discharge home from hospital (whichever is earlier).
Secondary	Maternal Outcome Set: Infant's birth weight z-score	Infants birth weight z-score.; This is a secondary outcome for Pregnancy Domains only.	At birth
Secondary	Maternal Outcome Set: Infant's gestational age at birth	Infant's gestational age at birth.; This is a secondary outcome for Pregnancy Domains only.	At birth
Secondary	Maternal Outcome Set: Number of maternal deaths	Death of the mother or pregnant person.; This is a secondary outcome for Pregnancy Domains only.	After trial entry and within 42 days postpartum
Secondary	Maternal Outcome Set: Number of participants with severe maternal morbidity Maternal Outcome Set: Severe maternal morbidity	Includes Intensive Care Unit (ICU) admission to an intensive care unit, sepsis, eclampsia, amniotic fluid embolism, pregnancy-related hysterectomy, severe primary postpartum haemorrhage, uterine rupture, cardiac arrest, mechanical ventilation (not for birth), stroke).; This is a secondary outcome for Pregnancy Domains only.	After trial entry and within 42 days postpartum
Secondary	Maternal Outcome Set: Length of maternal hospitalisation, in days	Number of days from trial entry to hospital discharge, in days. An average of three weeks.; This is a secondary outcome for Pregnancy Domains only.	From date of trial entry to date of discharge home from hospital (or date of death, whichever occurs earlier), assessed up to 12 months.
Secondary	Maternal Outcome Set: Number of participants readmitted to hospital	Readmission to hospital (any reason) after first hospital discharge and before 42 days postpartum.; This is a secondary outcome for Pregnancy Domains only.	After trial entry AND after first discharge home from hospital AND within 42 days postpartum. Measured at 42 days postpartum, YES/NO and reason for re-admission.
Secondary	Maternal Outcome Set: Mode of birth	Includes: vaginal birth, assisted vaginal birth, caesarean.; This is a secondary outcome for Pregnancy Domains only.	At birth